Inflammatory serum factors from aortic valve stenosis patients modulate sex differences in valvular myofibroblast activation and osteoblast-like differentiation.
Inflammatory serum factors from aortic valve stenosis patients modulate sex differences in valvular myofibroblast activation and osteoblast-like differentiation.
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DOI：
10.1039/d2bm00844k
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发表时间：
2022-11-08
影响因子：
6.6
通讯作者：
Aguado, Brian A.
中科院分区：
文献类型：
--
作者：
Vogt, Brandon J.;Peters, Douglas K.;Anseth, Kristi S.;Aguado, Brian A.
主动脉瓣狭窄（AVS）是一种由主动脉瓣叶纤维化和钙化引起的性二型心血管疾病。存在于来自AVS患者的血清中的循环炎症因子被认为通过驱动瓣膜间质细胞（VIC）活化成肌成纤维细胞和/或成骨细胞样细胞而促成瓣膜纤维钙化的性别差异。然而，炎症因子导致性别特异性瓣膜纤维钙化的分子机制仍不清楚。在这项研究中，我们确定了存在于AVS患者血清样本中的炎症因子，这些因子调节性别特异性肌成纤维细胞活化和成骨细胞样分化。在将血清蛋白质组数据集与临床和体外肌成纤维细胞数据集相关联后，我们将膜联蛋白A2和胱抑素C鉴定为与体外AVS患者严重程度和肌成纤维细胞活化测量值相关联的候选炎症因子。利用水凝胶生物材料作为模拟瓣膜细胞外基质的细胞培养平台的验证实验证实，膜联蛋白A2和胱抑素C通过p38 MAPK信号传导促进肌成纤维细胞的性别特异性维克活化。此外，膜联蛋白A2和胱抑素C主要在男性VIC中增加成骨细胞样分化。我们的研究结果暗示血清炎症因子作为潜在的AVS生物标志物，通过驱动维克肌成纤维细胞活化和/或成骨细胞样分化，也有助于性二态性AVS进展。总的来说，本文的结果进一步加深了我们对性别如何影响炎症驱动的AVS的整体理解，并可能导致性别特异性药物治疗策略的发展。确定和验证炎症血清因子作为水凝胶上性别特异性瓣膜间质细胞表型的驱动因素。
Aortic valve stenosis (AVS) is a sexually dimorphic cardiovascular disease that is driven by fibrosis and, often, calcification of the aortic valve leaflets. Circulating inflammatory factors present in serum from AVS patients are thought to contribute to sex differences in valve fibro-calcification by driving the activation of valvular interstitial cells (VICs) to myofibroblasts and/or osteoblast-like cells. However, the molecular mechanisms by which inflammatory factors contribute to sex-specific valve fibro-calcification remain largely unknown. In this study, we identified inflammatory factors present in serum samples from AVS patients that regulate sex-specific myofibroblast activation and osteoblast-like differentiation. After correlating serum proteomic datasets with clinical and in vitro myofibroblast datasets, we identified annexin A2 and cystatin C as candidate inflammatory factors that correlate with both AVS patient severity and myofibroblast activation measurements in vitro. Validation experiments utilizing hydrogel biomaterials as cell culture platforms that mimic the valve extracellular matrix confirmed that annexin A2 and cystatin C promote sex-specific VIC activation to myofibroblasts via p38 MAPK signaling. Additionally, annexin A2 and cystatin C increased osteoblast-like differentiation primarily in male VICs. Our results implicate serum inflammatory factors as potential AVS biomarkers that also contribute to sexually dimorphic AVS progression by driving VIC myofibroblast activation and/or osteoblast-like differentiation. Collectively, the results herein further our overall understanding as to how sex may impact inflammation-driven AVS and may lead to the development of sex-specific drug treatment strategies. Identify and validate inflammatory serum factors as drivers of sex-specific valvular interstitial cell phenotypes on hydrogels.
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影响因子：
5.2
作者：
de Arellano, Maria Luisa Barcena;Pozdniakova, Sofya;Regitz-Zagrosek, Vera
通讯作者：
Regitz-Zagrosek, Vera
DOI：
10.1161/atvbaha.120.315261
发表时间：
2020-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Grim JC;Aguado BA;Vogt BJ;Batan D;Andrichik CL;Schroeder ME;Gonzalez-Rodriguez A;Yavitt FM;Weiss RM;Anseth KS
通讯作者：
Anseth KS
DOI：
10.2215/cjn.00840208
发表时间：
2008-11-01
影响因子：
9.8
作者：
Groesbeck, Darcy;Koettgen, Anna;Furth, Susan
通讯作者：
Furth, Susan
影响因子：
5.3
作者：
Kaden, JJ;Dempfle, CE;Borggrefe, M
通讯作者：
Borggrefe, M
影响因子：
2.3
作者：
Goleski, Patrick J.;Reisman, Mark;Don, Creighton W.
通讯作者：
Don, Creighton W.